6

Finding Solutions: Options and Systemic Approaches
1

This session, chaired by Michael J. Brennan, Senior Advisor for Global Affairs, Aeras, underscored many of the barriers to harmonization and more efficient operation of biomedical product regulatory authorities and provided potential solutions from the perspective of different stakeholder representatives. The discussion offered additional attention to regulatory strategies promoting development and use of products for tropical diseases.

The discussion and the suggestions that conclude this chapter were directed to the principal challenges facing drug regulatory systems worldwide, including the need to foster collaboration and cooperation, reduce duplication of efforts through mutual trust and recognition, increase regulatory capacity and implementation effectiveness, and make the best uses of limited resources.

LEGAL FRAMEWORK

Numerous times in this workshop the existence of a common legal (and economic) framework in the European Union was cited by par-

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1 This chapter is based on brief presentations made by a reactor panel that included Vincent Ahonkhai, Deputy Director, Regulatory Affairs, BMGF; Raymond Chua, Group Director, Health Products Regulation Group, Singapore Health Sciences Authority; Mary Lou Valdez, Associate Commissioner, International Programs, and Director, Office of International Programs, FDA; David Wood, Coordinator, Quality, Safety and Standards, WHO; and discussions of workshop participants.



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6 Finding Solutions: Options and Systemic Approaches1 This session, chaired by Michael J. Brennan, Senior Advisor for Global Affairs, Aeras, underscored many of the barriers to harmoni- zation and more efficient operation of biomedical product regulatory authorities and provided potential solutions from the perspective of different stakeholder representatives. The discussion offered additional attention to regulatory strategies promoting development and use of products for tropical diseases. The discussion and the suggestions that conclude this chapter were directed to the principal challenges facing drug regulatory systems world- wide, including the need to foster collaboration and cooperation, reduce duplication of efforts through mutual trust and recognition, increase regu- latory capacity and implementation effectiveness, and make the best uses of limited resources. LEGAL FRAMEWORK Numerous times in this workshop the existence of a common legal (and economic) framework in the European Union was cited by par- 1  This chapter is based on brief presentations made by a reactor panel that included Vincent Ahonkhai, Deputy Director, Regulatory Affairs, BMGF; Raymond Chua, Group Director, Health Products Regulation Group, Singapore Health Sciences Authority; Mary Lou Valdez, Associate Commissioner, International Programs, and Director, Office of Inter- national Programs, FDA; David Wood, Coordinator, Quality, Safety and Standards, WHO; and discussions of workshop participants. 57

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58 INTERNATIONAL REGULATORY HARMONIZATION ticipants as facilitating the harmonization of drug regulations in member countries. Such frameworks do not exist in all regions, or even in all coun- tries, and their lack is frequently perceived as a stumbling block. In places where governments lack legal frameworks that would per- mit them to implement international norms and standards, harmonization becomes difficult. But “different countries have different needs, interests, and expectations from their global engagement,” said Mary Lou Valdez, Associate Commissioner, International Programs, and Director, Office of International Programs, FDA. At the very least, she said, a framework can establish minimums for what the country’s regulatory system should do, and, if it cannot or does not do them, some accountability mechanism should come into play. “Regulators should not worry about getting out ahead of their gov- ernments,” said Peter Barton Hutt, Covington & Burling, LLP, a workshop attendee. “It is the duty of regulators to use creativity and leadership, not to worry about their statutory authority.” For example, he noted, some of FDA’s most important harmonization efforts were not created by statute or were legislated after the regulators invented them. COOPERATION AND COLLABORATION Raymond Chua, Group Director, Health Products Regulation Group, Singapore Health Sciences Authority, noted that in the drug regulatory field, PIC/S2 has developed an informal cooperation scheme which aims to encourage member states to recognize each others’ inspections, har- monize good manufacturing practice requirements, train inspectors, exchange information, and engender mutual confidence. An area where greater cooperation may be emerging is work sharing. One workshop participant noted that various developed nations’ regula- tory authorities are looking to work share around issues that arise in the premarket phase of generic drug development. Work sharing plans and joint plans of action also could be useful in expanding the regulatory sci- ence base for products going to the least resourced countries. An area ripe for collaboration is data sharing. Developing secure information platforms where data can remain confidential is a challenge, but are essential to cooperative work, said one workshop participant. Some data-sharing efforts are taking place, but unless there is a collabora- 2  Themission of PIC/S, which are two international instruments between countries’ phar- maceutical inspection authorities, is “to lead the international development, implementation and maintenance of harmonised Good Manufacturing Practice (GMP) standards and qual- ity systems of inspectorates in the field of medicinal products.” For more information, see http://www.picscheme.org (accessed April 22, 2013).

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FINDING SOLUTIONS: OPTIONS AND SYSTEMIC APPROACHES 59 tive Memorandum of Understanding across agencies, they can be difficult to accomplish. For example, Lembit Rägo, WHO, noted that WHO has developed a SharePoint platform for exchanging inspection results among a certain set of countries. The hope in developing it, he said, was that shared inspection plans and reports would encourage more risk-based approaches to inspections. However, the countries involved have been slow to add data due to persistent unwillingness to have joint inspections or coordinated inspection plans. Beyond sharing information across agencies, several workshop partic- ipants suggested that increased discussion and collaboration with manu- facturers might lead to the industry’s better understanding of a country’s biomedical product needs, and the regulators’ better understanding of the policies and practices that would support the companies that are developing these priority products. One example of a regulatory action supporting industry would be harmonized clinical trial regulations for multinational research. Collaboration, cooperation, and networking need to be built into institutional structures as someone’s job, or the efforts stall out, said Rägo. At the same time, he said, it needs to be recognized that collaborative activities often come on top of a regulator’s already-full plate. Collaborat- ing effectively is not necessarily an obvious capacity need or something at which people are naturally good. Time and effort may need to go into figuring out what the best practices are in this arena. MUTUAL TRUST AND RECOGNITION Many activities support harmonization, including information shar- ing, effective communication, and the cooperative work that generates trust and confidence, said Valdez. Convergence will depend on building mutual trust among regulatory authorities so there can be some reliance on the decisions or input from peers. Mutual trust also is an essential precondition to joint activities. A good example of where that is working (cited by several workshop par- ticipants and speakers) is AVAREF, which brings together both regulators and national ethics committees from 19 countries to resolve issues in mul- tinational clinical trials. FDA, EMA, and Health Canada also participate, along with industry, which describes new products in their pipelines. David Wood, Coordinator, Quality, Safety and Standards, WHO, noted that in the forum, participants can hear what the problems are, who is doing what, and come to appreciate the quality of the input from regula- tors in neighboring countries. In this way, he said, AVAREF is both an information-gathering and trust-building model that might be expanded. The Singapore Health Sciences Authority uses a mutual recognition

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60 INTERNATIONAL REGULATORY HARMONIZATION system for its approvals of new drugs, Chua explained. Under its system, manufacturers need to go through a full dossier approval process only for those products that have not been evaluated by any of the Health Sciences Authority’s approved reference agencies. If the drug has been approved by one of these agencies, the new drug undergoes an abridged review, which has a shorter time line. If at least two of these agencies have approved the drug, it goes through a verification process, which is the shortest. Both of the latter processes are called confidence-based approaches. Another challenge to harmonization, often not mentioned, is public trust, said Toshiyoshi Tominaga, Osaka City University Hospital. Even if regulators want to accept the findings of another national or international authority, they also need to satisfy the public, he said. As a consequence, public education and transparency of the decision-making process are essential, and regulators need to balance the need to accommodate the public’s concerns with the costs of reinventing the wheel. CAPACITY BUILDING Not every country can have the staff and other resources of the world’s largest biomedical products regulatory agencies. Although the relatively well-resourced agencies have a different scope of problems than lower income countries, they are reaching out to help build capacity elsewhere. The less well-resourced countries need to determine what level of regulatory activity is sufficient in their particular circumstances, and what their priorities are, so that the help that is available can be directed to the areas of greatest need, said Vincent Ahonkhai, BMGF. By working together, regulators in a region can allocate priorities across countries, so that across a group of countries, the most important work is being done by the group as a whole. One priority might be filling gaps particular to a region that the larger regulatory authorities have not addressed—such as vaccine stability at higher temperature and humid- ity levels, said Ahonkhai. Similarly, by not duplicating elements of the drug approval process that other regulatory agencies have completed, a local agency can focus on postmarketing surveillance within its popula- tion. Setting priorities will require the lower income countries to make trade-offs, said Ahonkhai; sovereignty is important, but having effective vaccines and access to approved medicines also are important. A need here is to identify the best ways to build capacity that take advantage of networks already in place, in addition to building capacity in the net- works themselves. Wood noted that WHO has found institutional development plans a helpful tool in evaluating local regulatory entities. These plans are devel-

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FINDING SOLUTIONS: OPTIONS AND SYSTEMIC APPROACHES 61 oped based on peer audits that assess the agency’s systems, structure, and functions against a set of established criteria, which can be stratified to indicate which functions are appropriate for a given set of circumstances. (Participating on a peer audit team—which comprises both experienced and novice peers—is an educational experience in itself, he said.) The result is an evidence-based plan for further agency development that enables focused capacity-building efforts. For example, the plan identi- fies what the real training needs are and who needs to be trained to meet them. Ideally, said Wood, an institutional development plan needs the approval of higher governmental authorities in order to obtain the broad support and sustainability needed for capacity-building efforts. WHO’s Global Vaccine Action Plan brought together experts in eco- nomic development, health, and immunization, along with other stake- holders.3 One of the goals of the plan, endorsed by the World Health Assembly’s 194 member states in May 2012, is to “introduce new and improved vaccines and spur research and development for the next gen- eration of vaccines and technologies.” Its implementation requires a paral- lel regulatory agenda, which has been developed by a working group and is in publication, reported Wood. Valdez noted that differential implementation of standards remains a significant barrier to harmonization. Aside from the problem of differ- ences in technical capacity, some countries lack the essential legal and policy platforms that would facilitate implementation and assessment of impact. Thus, the notion of capacity building needs to include scientific capacity, legal capacity, and measurement capacity, she said. The question of capacity development has no single answer because there is no single motive for it. In a broad sense, the kind of capacity needed is capacity for collaboration, cooperation, and understanding of the global regulatory situation. Capacity building per se does not solve the problems, said Rägo, “You have to know capacities for what and where and when.” BUSINESS CASE Although the benefits of international harmonization of medical products regulation may be clear to experts in the field, these benefits are not as clear to everyone else, said Wood. Nor is it uniformly evident to policy makers that resources should be devoted to the effort. Wood pointed out that WHO has commissioned some inquiry into how donors feel about supporting harmonization efforts, and learned they do not 3  See http://www.who.int/immunization/global_vaccine_action_plan/en/index.html (accessed April 10, 2013).

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62 INTERNATIONAL REGULATORY HARMONIZATION understand why they should support them. They believe the regulatory bodies promoting harmonization are slowing down the process of making medical products accessible. Moreover, many stakeholders believe that ICH is managing these issues, but the workshop’s discussions revealed that ICH’s efforts, while necessary to the process of harmonization, are not sufficient. The first step, then, may be to make a stronger case for why harmo- nization is important. Valdez emphasized the need to develop a business case that demonstrates how key actions discussed at the workshop—such as ensuring supply chain integrity, data transparency, data sharing, phar- macovigilance, and use of science-based standards—would save money and increase the efficiency of regulators and industry alike. While regu- lators’ strength is in leading with the science, she said, they do not do especially well in making an economic argument. Some solid efficacy cases—examples of how a harmonized system is a good investment—may already exist. For example, James Fitzgerald, PAHO, WHO, noted that Mexico’s Federal Commission for the Protection against Sanitary Risks has demonstrated that institutional plans, changed management, and linkages with reference agencies can have an enormous positive economic impact on the pharmaceutical sector and reduce the costs of regulation. Several speakers agreed that more fundamentally, what is needed is a greater understanding of the importance of regulatory work. Regulators have not been particularly effective in positioning the imperative for regu- latory systems in the broader public health dialogue. For example, Valdez noted that recent WHO discussions about the public health workforce did not include the regulatory workforce. “We are also not very good about really positioning the imperative for regulatory systems in even the broader global public health dialog,” she added. TOP-LEVEL SUPPORT Several workshop participants noted that the highest management level in the regulatory agencies, the level that makes resourcing decisions for projects, need to be involved in discussions about the importance of harmonization. In turn, the business case has to be understood by the government officials to whom these leaders report. Valdez added that ministries of trade and foreign affairs, as well as development assistance agencies, need to understand how these types of investments will expand the strength and the base of a country’s economy. The economic case has to represent advantages not just to the larger markets, but also to leaders in the smaller ones. There is a risk that economic arguments will be interpreted as the larger economies’ desire

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FINDING SOLUTIONS: OPTIONS AND SYSTEMIC APPROACHES 63 for access to the smaller markets, said Fitzgerald, with all the economic benefits accruing to the major players. He suggested that WHO and PAHO might serve as honest brokers between the countries with reference systems and those without. At present, for example, El Salvador links to Mexico’s registration process; and Mexico links to FDA. Top-level support can have many benefits, in addition to the obvi- ous potential resource benefits. Political capital is important, as well, and can become advance efforts to promote data sharing, for example. One cautionary note sounded by Chua was that the need for top-down endorsements does not obviate the need for bottom-up assessments of the practicality of a given harmonization effort. META-HARMONIZATION A robust area of harmonization is in standards development, with strong engagement by government, industry, and other groups. But because different groups have proposed different standards and guid- ances, many workshop participants supported the idea of harmonizing these harmonization efforts. Are these standards duplicative or comple- mentary? Are they different enough or adopted differently enough that they create confusion or actual impediments to implementation? Alter- natively, do they expand the reach of regulatory science in ways that can build trust and create efficiencies? Although a great deal of work has gone into creating a large number of harmonized standards, several participants noted that too little atten- tion has been paid to making sure they are implemented effectively, if at all. Wood said the examples built into some standards of how they should be applied are helpful, but do not go far enough. He noted that WHO has developed workshops for people in the field about its new stan- dards. Also, it has worked with industry partners who have contributed real data for case studies about how the standard could be applied. The combination of illustrative case studies and interaction with regulators in the field begins to move implementation along, said Wood, and in a more harmonized way. Not only are regulators working in silos defined by the different regulatory harmonization issues and organizations, but silos also exist for product lines, such as vaccines, pharmaceuticals, generics, devices, and so on, added Mike Ward, Health Canada. Considering the role of the regulator in the 21st century, Moheb M. Nasr, Vice President, CMC Regulatory Strategy, GlaxoSmithKline, asked, “Is it to micromanage and evaluate development and manufacturing, or is it to assure quality, safety, and efficacy?” Focusing on the key regulatory functions perhaps needs to precede moving into harmonization, he said,

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64 INTERNATIONAL REGULATORY HARMONIZATION or all the discussions about capacity building and enhancing activities will focus on very narrow issues. SUGGESTIONS FOR MOVING FORWARD One comprehensive suggestion for increasing harmonization was offered by Chua in his presentation, while other presenters and partici- pants made a number of additional suggestions. Chua proposed development of an international regulatory organiza- tion similar to that of the International Civil Aviation Organization (ICAO) or IAEA (see Box 6-1) that would generate the necessary political will from health, trade, and economic reasons and common vision to achieve world- wide adoption. Within the global organization would be smaller working subcommittees that could address specific areas, such as premarketing evaluation, pharmacovigilance, or building on the work PIC/S has done in good manufacturing practices. This three-part approach—premarket- ing, manufacturing, pharmacovigilance—would cover the whole lifecycle of a pharmaceutical product. The proposed organization would require stable funding, a mechanism for random audits to ensure standards are being met, and ongoing robust governance oversight for sustainability reasons, said Chua. According to Chua, the governance structure could be based on an expansion of current ICH or WHO platforms, or be housed in a separate organization, although that might best be avoided. Too many overlapping structures, agencies, and organizations have developed over the years that were not well aligned, with much duplication of effort, meetings, and so on. Smaller groups could be formed as needed at the regional or subregional levels or laterally, looking at consistency and alignment across regions. Compared to regulatory or legislative changes, standards and guide- lines would be easier to achieve, as of now, because they do not intrude on national sovereignty rights. ICAO has approached this by setting man- datory global minimum standards, and the biomedical products industry could do the same, with the addition of a second set of standards that responds to any specific local or regional needs. An example of standards that could not be completely harmonized would be those for drugs used in the tropical region, which might require separate stability studies. The next step would be to adopt implementation plans that move countries toward harmonization and convergence. Harmonization, more or less, refers to synchronization of standards, whereas convergence refers to meetings of practices and process, said Chua. Hence, similar to the operation of PIC/S, the approach might be that if a product is approved by the international organization, it can be used everywhere in the world,

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FINDING SOLUTIONS: OPTIONS AND SYSTEMIC APPROACHES 65 BOX 6-1 Examples from Other Industriesa The banking, aviation, and atomic energy industries all achieved harmonization sooner, more quickly, and in a much more coherent manner than has the biomedi- cal products industry. IAEA—which for historical and political reasons is not a UN specialized agency, but nevertheless reports annually to the UN General Assembly and, as needed, to the Security Council—is charged with several roles that again are roughly parallel to the roles of biomedical products regulation. In broad terms, IAEA resources are directed to promoting sustainable development, catalyzing innovation, building capacity in energy planning and analysis, protecting people from harm, and help- ing countries improve their scientific and technological capabilities. The agency works across national borders in carrying out these roles, a requirement of which is harmonizing the work of many countries. ICAOb is a UN specialized agency, based in Montréal, Canada, that serves as a global forum for 191 member states that have signed the relevant treaties (the current, 9th edition, of the Convention on International Civil Aviation is referred to as “the statute”). ICAO’s purpose is to promote the safe and orderly development of international civil aviation throughout the world. It engages in many activities that parallel those of drug regulatory authorities: determining priorities, developing policies and standards, coordinating global monitoring, delivering targeted assis- tance, and building capacity. Its planning work—from the global safety level down to regional and national safety plans—is based on high-level principles accepted by industry stakeholders. It provides a step-by-step guide to help those at the regional or subregional level to implement their safety enhancement plans. Even though the aviation industry is a relatively safe one, ICAO develops precise safety targets aimed at continually strengthening safety programs. ICAO has a mechanism to ensure that its safety plan is kept updated in a coordinated way. Flight Safety Information Exchange websitec allows full transpar- ency: Anyone can access its worldwide aviation safety information. Cooperation among member states and the regulators is vital for maintaining these resources. ICAO standards include “any specification for physical characteristics, configu- ration, material, performance, personnel or procedure, the uniform application of which is recognized as necessary for the safety or regularity of international air navigation.”d The governments that contract with ICAO must comply with these standards, in accord with the ICAO Convention, or tell the agency why they cannot. Adherence to the standards is audited by ICAO. a This box is based on the presentation by Raymond Chua, Group Director, Health Products Regulation Group, Singapore Health Sciences Authority. b See http://www.icao.int/Pages/default.aspx (accessed April 10, 2013). c See http://legacy.icao.int/fsix (accessed April 10, 2013). d See http://legacy.icao.int/icao/en/anb/mais/index.html (accessed April 10, 2013).

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66 INTERNATIONAL REGULATORY HARMONIZATION again, unless there are distinct regional requirements. Such a system would require the mutual trust and confidence of the regulators, as well as the public. Chua summarized the steps needed as the six Cs: commitment, con- vergence, communication, cooperation, collegiality, and capacity. In addition to Chua’s comments, various individual workshop participants had the following insights about moving forward with harmonization: • Progress requires two essential preconditions: developing strategic and more structured regulatory frameworks and creating a safe space for discussion. • To support the business case, people need to be able to demon- strate the importance of harmonization investments and to advo- cate for them. • With respect to standards implementation, it would be helpful to create an Internet-based information exchange about ideas that have and have not worked. • Building in certain incentives for international harmonization is also important, as well as ensuring sustainable ways to measure implementation and update of harmonization. • Numerous models are being used to increase regulatory capac- ity, and it would be useful to create an inventory of them that describes their core operating principles and drivers, strengths and weaknesses, and information on their usefulness. Less developed countries could use the inventory to see which models best fit their needs and their environments. Likewise, networks could consider whether to adopt any of the principles used by others. • An international regulatory cooperative development plan, with perhaps a secretariat at its hub, could support and coordinate var- ious current harmonization initiatives. At present, for example, separate initiatives on generics and biosimilars are addressing the same issues and might productively collaborate. • Examining best practices from other industries continues to be helpful in sparking new ideas.